Unravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay
Serena L. Y. Teo,
Joshua J. Rennick,
Daniel Yuen,
Hareth Al-Wassiti,
Angus P. R. Johnston () and
Colin W. Pouton ()
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Serena L. Y. Teo: Monash Institute of Pharmaceutical Sciences, Monash University
Joshua J. Rennick: Monash Institute of Pharmaceutical Sciences, Monash University
Daniel Yuen: Monash Institute of Pharmaceutical Sciences, Monash University
Hareth Al-Wassiti: Monash Institute of Pharmaceutical Sciences, Monash University
Angus P. R. Johnston: Monash Institute of Pharmaceutical Sciences, Monash University
Colin W. Pouton: Monash Institute of Pharmaceutical Sciences, Monash University
Nature Communications, 2021, vol. 12, issue 1, 1-12
Abstract:
Abstract Cytosolic transport is an essential requirement but a major obstacle to efficient delivery of therapeutic peptides, proteins and nucleic acids. Current understanding of cytosolic delivery mechanisms remains limited due to a significant number of conflicting reports, which are compounded by low sensitivity and indirect assays. To resolve this, we develop a highly sensitive Split Luciferase Endosomal Escape Quantification (SLEEQ) assay to probe mechanisms of cytosolic delivery. We apply SLEEQ to evaluate the cytosolic delivery of a range of widely studied cell-penetrating peptides (CPPs) fused to a model protein. We demonstrate that positively charged CPPs enhance cytosolic delivery as a result of increased non-specific cell membrane association, rather than increased endosomal escape efficiency. These findings transform our current understanding of how CPPs increase cytosolic delivery. SLEEQ is a powerful tool that addresses fundamental questions in intracellular drug delivery and will significantly improve the way materials are engineered to increase therapeutic delivery to the cytosol.
Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23997-x
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DOI: 10.1038/s41467-021-23997-x
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